Assessment of Anthropometric Indices in Patients with Phenylketonuria.

Objectives Dietary phenylalanine restriction is the main treatment of phenylketonuria (PKU, OMIM 261600). There are a number of studies which have demonstrated growth retardation in these patients, and some are in contrast. This study was performed to assess the growth parameters of treated PKU patients. Materials & Methods This cross-sectional study was performed between 2015 and 2017 to compare growth indices in PKU patients in our clinics with normal age and sex matched controls. Weight, height, head circumference (HC), weight for height and BMI (weight/height2) were measured and converted into Z-scores. We assessed differences between patients and controls’ anthropometric indexes in all patients and separately in patients who were diagnosed by newborn screening program and patients who were diagnosed after presentation of clinical manifestations in comparison with age and sex-matched controls. Also, this difference was assessed separately in patients aged two years and less. Correlations between pretreatment plasma phenylalanine concentrations mean plasma phenylalanine concentrations and anthropometric parameters were analyzed in the patients. Results Overall, 209 under-treatment PKU patients (103 males, 106 females; mean age 9.29 ± 8.7 years) and 216 controls (109 males and 107 females; mean age 8.98 ± 8.62 years) matched in terms of age, sex and birth weight were enrolled in this study. In general, 130 patients were diagnosed by newborn screening and 79 were diagnosed when they became symptomatic before the screening program. A significant difference (p=0.000) was found only in HC z-score and weight for height z-score in comparison with the control group, when we assessed all patients. We did not find any significant differences in any of the anthropometric indexes between cases and controls who were aged 2 years old and less. Head circumference SDS and weight for height SDS were significantly different when patients and controls who were more than 2 years old were compared. Mean HC was significantly lower in patients, while BMI SDS, weight SDS, and weight for height SDS were significantly higher in PKU patients in comparison with the control group when patients who were diagnosed in newborn screening were assessed. Head circumference SDS, BMI, height SDS and difference between patients’ height SDS and mid parental height SDS had significantly lower mean scores in comparison with those of the control group, while mean weight SDS was significantly higher compared to controls when patients who were diagnosed after clinical presentation were assessed. Mean phenylalanine was not correlated with anthropometric indices, while there was a correlation between pretreatment phenylalanine and HC. Conclusion: Disparities in anthropometric indexes changes observed in different studies may be due to diverse diet protocols, availability of various specific products and micronutrient substitutes.

remain (1,2). Also, adhering to this kind of diet results in a number of complications such as micronutrients, minerals, vitamins and essential fatty acids deficiency; thus, each patient's dietary habits should be considered to acquire milestones and have a normal growth (3)(4)(5).
Several studies have been designed for the assessment of growth in PKU patients and finding the effects of Phe-restricted diet on physical growth of PKU patients under treatment, but inconsistent findings have been achieved (6)(7)(8)(9)(10).
Herein, we measured growth parameters, weight for height and BMI in patients who were under Phe-restricted diet. We also considered familial and constitutional short stature in these patients.

Material & Methods
This cross-sectional study was performed from 2015 to 2017 in PKU clinics in Mofid Children's Hospital, where the patients were followed up (a referral hospital). We considered a patient to have PKU if plasma phenylalanine concentrations were > 6 mg/dl in untreated newborn infants (child). The study was approved by the Ethics Committee of Shahid Beheshti University of Medical Sciences.
Z-score of head circumference (HC), body mass index (BMI: weight/height 2 ), weigh, and height were compared between PKU patients matched in terms of age, sex and birth weight. We selected age and sex-matched controls from normal children who visited our endocrine clinics for following their growth and they are completely normal without any underlying or chronic diseases. For participants with age? more than 20 years, we selected controls from our medical staff and medical students.  (12). Dietary Phe intake was adjusted to achieve blood Phe levels between 2-6 mg/dl in patients <12 years old and between 2-10 mg/dl in patients >12 years old (13). This level of control was considered as appropriate, and blood Phe less than 2 mg/dl was considered as overtreatment (13). Plasma Phe concentrations were measured by the fluorometric method, which is a quantitative and precise method (14). The mean of plasma Phe concentration for each patient was calculated, considering the maximum Phe measurements throughout a year.
Informed consent was obtained orally from the parents and patients who were mature and not mentally retarded.
We also compared anthropometric measures with those of the control group separately for patients who were diagnosed in screening and patients who were diagnosed after presentation of clinical signs and symptoms, we also compared anthropometric indexes in patients who were equal or less than 2 years old and patients who were more than 2 years old with the age-matched control group separately.

Statistical Method
This cross-sectional study was performed from 2015 to 2017 in PKU clinic affiliated to Mofid Children's Hospital.
Data were analyzed in SPSS version 22.

Distribution of values assessed by One Sample
Kolmogorov-Smirnov test and distribution of all values were abnormal, except for midparental height z-score. Mann-Whitney test was used for analyzing the data. P-value (predictive value) <0.05 was considered statistically significant.
We used correlation analysis to assess the effect of pretreatment and intratreatment phenylalanine levels on anthropometric indexes.

Results
Overall, 209 PKU patients (103 males, 106 females; mean age 9.29 ± 8.7 years, range 1 month to 44 years) were enrolled in our study. In general, 130 patients were diagnosed by newborn screening and 79 patients were diagnosed when they became symptomatic before the screening program.
Our control group consisted of 216 age and sex-

PKU patients and the control group in HC SDS
(z-score) and weight for height SDS (P=0.000 for both variables). Mean HC in the PKU patients was -0.68± 1.34 cm, whereas this value was 0.081± 0.94 cm in the control group. Mean weight for height z-score in the PKU patients was 1.21± 2.05, whereas this value was 0.51± 1.76 in the control group (Table1). We did not find any significant differences in weight SDS, BMI SDS, and height SDS between the cases and controls. Difference between patients' height SDS and midparental height SDS was not significantly different in patients (mean ± SD: 1.9±1.14) and the control group (mean ± SD: 2±1.05) (P=0.81).

Phenylketonuria patients 2 years old and lower versus age and sex-matched controls
Weight SDS, height SDS, weight for height SDS, and HC SDS were compared between PKU patients who were less than 2 years old and age and sex matched controls. We did not find any statistically significant difference in any of the anthropometric indexes between cases and controls. Descriptive statistics are summarized in Table 2 Table 3.

Pretreatment and mean plasma phenylalanine concentrations
The mean of patient's pretreatment phenylalanine were fewer children lower and higher than 10th and 90th weight for height percentile than expected (25).
However, no statistically significant difference between PKU patients and controls was reported by Huemer (7). Dobbelaere et al. also found body composition was not different from that of controls matched for age and sex (18).
Another interesting result in our study was absence of correlation between mean phenylalanine level during treatment and growth indexes; however, pretreatment phenylalanine level had a negative correlation HC SDS in patients.
In Conclusion, The most important anthropometric index that was affected in PKU patients was HC, especially in patients with more than 2 years of age in spite of the fact that patients were under Phe restriction diet. Significantly higher weight z-score, BMI z-score, and weight for height z-score were seen in patients who were under early onset nutritional treatment probably because of low protein and high carbohydrate diet. Height z-score and BMI z-score were significantly lower in patients diagnosed after clinical presentation probably because of the existing sequels affecting nutrition and activity of patients, while weight SDS was significantly higher. Differences in anthropometric index changes that observed in different studies may be due to disparate diet protocols, availability of various specific products and micronutrient substitution.